Graphical Abstract:

Abstract:

Intracellular calcium transients generated by activation of voltage-gated calcium (CaV)
channels generate local signals, which initiate physiological processes such as secretion, synaptic
transmission, and excitation-contraction coupling. Regulation of calcium entry through CaV channels
is crucial for control of these physiological processes. In this article, I review experimental results that
have emerged over several years showing that cardiac CaV1.2 channels form a local signaling complex,
in which their proteolytically processed distal C-terminal domain, an A-Kinase Anchoring Protein,
and cyclic AMP-dependent protein kinase (PKA) interact directly with the transmembrane core
of the ion channel through the proximal C-terminal domain. This signaling complex is the substrate
for β-adrenergic up-regulation of the CaV1.2 channel in the heart during the fight-or-flight response. Protein phosphorylation
of two sites at the interface between the distal and proximal C-terminal domains contributes importantly to control of
basal CaV1.2 channel activity, and phosphorylation of Ser1700 by PKA at that interface up-regulates CaV1.2 activity in response
to β-adrenergic signaling. Thus, the intracellular C-terminal domain of CaV1.2 channels serves as a signaling platform,
mediating beat-to-beat physiological regulation of channel activity and up-regulation by β-adrenergic signaling in
the fight-or-flight response.

Abstract:Intracellular calcium transients generated by activation of voltage-gated calcium (CaV)
channels generate local signals, which initiate physiological processes such as secretion, synaptic
transmission, and excitation-contraction coupling. Regulation of calcium entry through CaV channels
is crucial for control of these physiological processes. In this article, I review experimental results that
have emerged over several years showing that cardiac CaV1.2 channels form a local signaling complex,
in which their proteolytically processed distal C-terminal domain, an A-Kinase Anchoring Protein,
and cyclic AMP-dependent protein kinase (PKA) interact directly with the transmembrane core
of the ion channel through the proximal C-terminal domain. This signaling complex is the substrate
for β-adrenergic up-regulation of the CaV1.2 channel in the heart during the fight-or-flight response. Protein phosphorylation
of two sites at the interface between the distal and proximal C-terminal domains contributes importantly to control of
basal CaV1.2 channel activity, and phosphorylation of Ser1700 by PKA at that interface up-regulates CaV1.2 activity in response
to β-adrenergic signaling. Thus, the intracellular C-terminal domain of CaV1.2 channels serves as a signaling platform,
mediating beat-to-beat physiological regulation of channel activity and up-regulation by β-adrenergic signaling in
the fight-or-flight response.